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dc.contributor.authorKwan, Daniel C.H.
dc.contributor.authorProle, David L.
dc.contributor.authorYellen, Gary
dc.date.accessioned2013-05-01T19:47:28Z
dc.date.issued2012
dc.identifier.citationKwan, Daniel C.H., David L. Prole, and Gary Yellen. 2012. Structural changes during HCN channel gating defined by high affinity metal bridges. The Journal of General Physiology 140(3): 279-291.en_US
dc.identifier.issn0022-1295en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10609663
dc.description.abstractHyperpolarization-activated cyclic nucleotide–sensitive nonselective cation (HCN) channels are activated by membrane hyperpolarization, in contrast to the vast majority of other voltage-gated channels that are activated by depolarization. The structural basis for this unique characteristic of HCN channels is unknown. Interactions between the S4–S5 linker and post-S6/C-linker region have been implicated previously in the gating mechanism of HCN channels. We therefore introduced pairs of cysteines into these regions within the sea urchin HCN channel and performed a Cd2+-bridging scan to resolve their spatial relationship. We show that high affinity metal bridges between the S4–S5 linker and post-S6/C-linker region can induce either a lock-open or lock-closed phenotype, depending on the position of the bridged cysteine pair. This suggests that interactions between these regions can occur in both the open and closed states, and that these regions move relative to each other during gating. Concatenated constructs reveal that interactions of the S4–S5 linker and post-S6/C-linker can occur between neighboring subunits. A structural model based on these interactions suggests a mechanism for HCN channel gating. We propose that during voltage-dependent activation the voltage sensors, together with the S4–S5 linkers, drive movement of the lower ends of the S5 helices around the central axis of the channel. This facilitates a movement of the pore-lining S6 helices, which results in opening of the channel. This mechanism may underlie the unique voltage dependence of HCN channel gating.en_US
dc.language.isoen_USen_US
dc.publisherThe Rockefeller University Pressen_US
dc.relation.isversionofdoi:10.1085/jgp.201210838en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434101/pdf/en_US
dash.licenseLAA
dc.titleStructural changes during HCN channel gating defined by high affinity metal bridgesen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalThe Journal of General Physiologyen_US
dash.depositing.authorYellen, Gary
dc.date.available2013-05-01T19:47:28Z
dc.identifier.doi10.1085/jgp.201210838*
dash.contributor.affiliatedYellen, Gary


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